The Role of Peroxisome Proliferator-Activated Receptors in Pulmonary Vascular Disease

Abstract

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily that regulate diverse physiological processes ranging from lipogenesis to inflammation. Recent evidence has established potential roles of PPARs in both systemic and pulmonary vascular disease and function. Existing treatment strategies for pulmonary hypertension, the most common manifestation of pulmonary vascular disease, are limited by an incomplete understanding of the underlying disease pathogenesis and lack of efficacy indicating an urgent need for new approaches to treat this disorder. Derangements in pulmonary endothelial-derived mediators and endothelial dysfunction have been shown to play a pivotal role in pulmonary hypertension pathogenesis. Therefore, the following review will focus on selected mediators implicated in pulmonary vascular dysfunction and evidence that PPARs, in particular PPARγ, participate in their regulation and may provide a potential novel therapeutic target for the treatment of pulmonary hypertension.

Effect of PPARγ inhibition on pulmonary endothelial cell gene expression: gene profiling in pulmonary hypertension

“…Based on previous findings that loss of PPAR␥ is associated with PH (2) and PPAR␥ activation with PPAR␥ agonists significantly reduces the PH phenotype in a variety of rodent models (18,34,35), we hypothesized that the global gene expression changes caused by PPAR␥ inhibition underlie the pulmonary vascular remodeling in PH. We found 100 genes and ESTs were upregulated by Ͼ1.5-fold and 21 genes and ESTs were downregulated by Ͼ1.3-fold in PPAR␥-inhibited PAEC (P Ͻ 0.05).…”

“…The decrease in NO and prostacyclin and the increase in ET-1, NADPH oxidase, and Rho/Rho kinase activity have been demonstrated to be important mediators of pulmonary vasoconstriction and thus play important roles in PH (35,39). However, our understanding of the pathogenesis of PH is far from complete as little is known about the onset of pulmonary vascular remodeling in this disease process.…”

“…However, our knowledge on the interplay between PPAR␥ and endothelial dysfunction is limited. It has been shown that decreases in PPAR␥ expression reduces nitric oxide (NO) production and induces abnormal EC and VSMC growth (4,35). However, the exact mechanisms underlying PPAR␥ downregulation and the pathogenesis of PH remain to be defined.…”

“…Recently, it has been shown that loss of PPAR␥ is associated with pulmonary hypertension (PH) (35). PPAR␥ expression has been shown to be significantly reduced in the plexiform lesions of human subjects with PH (2).…”

HO-1 Induced by Cilostazol Protects Against TNF-α-associated Cytotoxicity via a PPAR-γ-dependent Pathway in Human Endothelial Cells

“…It is also activated by synthetic ligands such as thiazolidinediones [3,4]. Activation of PPAR-γ inhibits the proliferation of vascular smooth muscle cells [5,6] and also has anti-inflammatory effects [7,8]. In addition, PPAR-γ plays a central role in regulating the expression of genes related to lipid trafficking, cell proliferation, and inflammatory signaling [9].…”